Pulmonary hypertension (PH) is a complex, progressive syndrome leading to right ventricular (RV) failure and death. RV dysfunction predicts morbidity and mortality in PH. Considerable variability exists in the RV hypertrophy and dysfunction that develops in patients with PH, suggesting susceptibility differences in the RV response to PH. little is known about the mechanisms that drive the RV response, and potential regulatory factors remain undetermined. The pluripotential cytokine MIF (macrophage migration inhibitory factor) has described roles in regulating changes in cardiomyocyte glucose metabolism observed in the pressure- overloaded RV in animal models of PH. Interestingly;the cytokine also has roles in the regulation of myocyte and vascular endothelial cell apoptosis, vascular smooth muscle cell prostacyclin synthesis, and vascular inflammation. Our preliminary studies show that chronic hypoxia induces MIF expression selectively in the RV of C57 BL/6 mice. Furthermore, MIF-deficient mice show diminished RV hypertrophy in response to chronic hypoxia. The studies proposed in the current application are designed to determine if MIF has a functional role in the regulation of the RV response to chronic hypoxia, potentially through its role in regulating myocyte glucose metabolism and energy supply. Specifically, we will define the mechanisms by which hypoxia induces MIF expression in RV of mice and in cardiomyocytes in vitro. We will subsequently use knockout mice with absent MIF expression to determine whether MIF is required for RV hypertrophy and/or dysfunction in response to hypoxia. Finally, we will measure activation of MIF-dependent signaling pathways involved in myocyte glycolysis and glucose uptake in wild type and MIF-null mice exposed to chronic hypoxia to determine whether the cytokine is required for metabolic regulation. These studies will establish a regulatory role for MIF in the RV response to PH, and may help to clarify the links between RV hypertrophy, metabolic change, ventricular dysfunction, and failure. In the long term, the proposed studies may be relevant to future studies designed to develop RV-specific therapies for PH. They may also identify MIF as a bio-marker in patients with PH to monitor progression to RV failure so that treatment strategies can be adjusted accordingly. PUBLIC HEALTH RELEVANCE: Project Narrative Pulmonary hypertension is a fatal syndrome that leads to right heart failure. Little is known about the basic mechanisms that regulate right heart failure in response to pulmonary hypertension. The proposed studies will investigate the function of a specific protein, MIF (macrophage migration inhibitory factor), in the regulation of right heart failure so that we may ultimately design more effective treatment strategies and disease monitoring techniques in patients with pulmonary hypertension.